This randomized phase II trial studies how well cabozantinib-s-malate works compared to sunitinib malate in treating patients with previously untreated kidney cancer that has spread to nearby areas or other parts of the body. Cabozantinib-s-malate and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cabozantinib-s-malate is more effective than sunitinib malate in treating patients with kidney cancer.

Overall survival (OS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

The primary analysis will be based on the stratified log-rank statistic to compare the two treatment arms on OS. The Kaplan-Meier product-limit estimator will be used to estimate OS distributions.

Progression free survival (PFS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

The primary analysis will be based on the stratified log-rank statistic to compare the two treatment arms on PFS. The Kaplan-Meier product-limit estimator will be used to estimate PFS distributions.

Secondary Outcome Measures:

Objective response rates [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

The Fisher exact test will be used to compare the two treatment arms.

Proportion of patients with unacceptable treatment related grade 3 or higher toxicity for all patients assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]

The Fisher exact test will be used to compare the two treatment arms.

Other Outcome Measures:

High MET expression (total MET and phospho/MET) by IHC [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Will determine if there is an association between high MET expression and better PFS and OS.

I. To determine if patients with renal cancer treated with cabozantinib (cabozantinib-s-malate) will have improved progression-free survival compared to patients treated with sunitinib (sunitinib malate).

SECONDARY OBJECTIVES:

I. To determine whether the response rate of patients with renal cancer treated with cabozantinib will be higher when compared with patients treated with sunitinib.

II. To determine whether patients with renal cancer treated with cabozantinib will have an improved overall survival when compared with patients treated with sunitinib.

TERTIARY OBJECTIVES:

I. To determine whether renal cancer patients with high met proto-oncogene (MET) expression by immunohistochemistry (IHC) have improvement in progression-free survival compared to patients with low MET expression on both arms of this study.

Eligible patients must be intermediate/poor risk, per the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (Heng) criteria; patients must therefore have as one or more of the following six factors:

No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days prior to registration

No prior systemic treatment for RCC; supportive therapies such as bisphosphonates (zoledronic acid) or denosumab are permitted

Patients must not have had a major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; however, patients who have had a nephrectomy may be enrolled 4 weeks after surgery, providing there are no wound-healing complications; the following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures

Radiation:

To the brain, thoracic cavity, abdomen, or pelvis must be completed at least 90 days before registration;

To bone must be completed at least 14 days before registration; and

To any other sites must be completed at least 28 days before registration In all cases, there must be complete recovery and no ongoing complications from prior radiation therapy

No chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors; patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration

Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan

No active brain metastases; patients with treated, stable brain metastases for at least three months are eligible as long as they meet the following criteria:

Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT); (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to registration are not eligible

Baseline brain imaging (MRI/CT) is required

No serious non-healing wound, ulcer, or bone fracture requiring intervention within 28 days prior to registration

No history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6 months prior to registration; note: patients with recent DVT who have been treated with therapeutic anticoagulation with low molecular weight heparin for at least 6 weeks are eligible; patients receiving therapeutic warfarin (> 2 mg/day) are not eligible; patients on warfarin may be switched to low molecular weight heparin at the discretion of the treating physician

No inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg systolic and/or >= 90 mmHg diastolic), or any prior history of hypertensive crisis or hypertensive encephalopathy

No corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization; note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard

No history of congenital QT syndrome

No unstable cardiac arrhythmia within 6 months prior to registration

No evidence of any of the following:

Clinically-significant gastrointestinal bleeding within 6 months before registration; or

Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before registration; or

Any other signs indicative of pulmonary hemorrhage within 3 months before registration

No uncompensated hypothyroidism; patients with hypothyroidism on therapy are required to have thyroid stimulating hormone (TSH) within normal limits

No radiologic or clinical evidence of pancreatitis

No history of organ transplant

Patients with active infection requiring systemic treatment within 28 days prior to registration are not eligible

Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:

Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)

Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2

Archival tissue must be available for submission, though it is optional for patients to choose to participate in the correlative sub studies

Absolute neutrophil count (ANC) >= 1,500/uL

Platelet count >= 100,000/uL

Hemoglobin >= 9 g/dL; patients may not have had a transfusion within 7 days prior to screening assessment

International normalized ratio (INR) =< 1.2 x ULN; subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation

TSH within normal limits (WNL); TSH only required for patients on thyroid supplementation

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01835158